The approximate 2½ pound human brain is comprised of the most complex material known to man. The neuron, the primary functional cell of the nervous system, operates on the basis of electrical impulses that result in the release of neurochemical substances (neurotransmitters) at specific receptors: dopamine, serotonin, acetylcholine, norepinephrine, gamma-amino butyric acid (GABA), and many others. There are estimated to be 80-100 billion (10 times the world population) neurons in the average human brain. These neurons, in turn, make 200-300 billion coded connections with other neurons to accomplish the complex tasks of the human body.
The brainstem serves as the vital pathway for relay and processing of neural impulses flowing continuously between the brain and the rest of the body. It is about the size of the thumb and contains the most dense and complicated wiring systems in the human body. In addition to the axons and dendrites (wires) that carry nerve impulses, the brainstem also contains critical nuclei that function as electrical generators and relays. Some of the nuclei are related to cranial nerve function while others serve as generators and impulse centers for pain perception, the autonomic system “fight or flight” response, wakefulness and alertness, as well as cardio-respiratory and related autonomic functions.
In the prior art, there have been previous attempts to provide for a more efficacious and safe treatment using serotonin agonists specific for the 5-HT1 receptor subtype.
For Example, U.S. Pat. No. 5,863,935 to Robertson et al. describes certain compounds having “5-HT1-like” receptor agonist properties and their administration in a number of ways, including topical or intranasal application.
Additionally, U.S. Pat. No. 5,805,571 to List, describes a transdermal therapeutic system for the systemic administration of active substances wherein at least one of the active substances listed is a serotonin agonist of the group comprising indole derivatives. Typically, transdermal systems are not used in acute situations because they do not provide an immediate effect, but rather provide prophylaxis or prolonged effect through their sustained delivery process. Transdermal systems such as that described in the '571 patent to List require a period of time for the drug to pass through a barrier layer and onto/into the skin (ionophoresis through concentrations gradients) which may take e.g., a substantial period of time until the dose of drug that is absorbed is sufficient to alleviate the pain associated with the headache. These previously described transdermal systems require the operation of a concentration gradient for the absorption of topically applied drug to enter the bloodstream through the small blood vessels in the skin and soft tissues. After entry into the systemic circulation in sufficient quantity to establish a therapeutic level, drug is eventually delivered by the cerebral blood flow to the target sites. Accordingly, this process involves relative considerable time, not amenable for the acute relief of symptoms. Furthermore, it is influenced by such factors as cardiac output and cerebrovascular disease that influence blood flow and tissue absorption.
The inventor has previously described the delivery of anti-migraine drugs (e.g., triptans and ergot alkaloids) and muscle relaxants (e.g., tizanidine) through topical regional neuro-affective (TRNA) therapy by topical application (e.g., as a cream/gel or a sustained release patch) applied at the back of the neck at the hairline (BONATH). The author has demonstrated the efficacy of this route of delivery for the treatment of migraine, another brainstem disorder, using sumatriptan and tizanidine compounded in an appropriate dermal penetration enhancing medium.
The inventor's previous U.S. Patent Publication No. 20030013753 (filed Jun. 5, 2002) and U.S. Patent Publication No. 20080090894, both of which are hereby incorporated by reference, disclose a unit dose of a topical formulation for treating a migraine or cluster headache comprising: a serotonin agonist incorporated into a pharmaceutically acceptable vehicle for topical administration onto the skin of a human patient. Preferably, the unit dose providing the serotonin agonist is in a form that is immediately absorbable when said unit dose is applied onto human skin. Preferably, the serotonin agonist comprises from about 0.5 to about 200 mg of sumatriptan, by weight based on the succinate salt, or a therapeutic equivalent dose of another topically absorbable pharmaceutically acceptable serotonin agonist. Preferably, the unit dose provides relief from a migraine or cluster headache within about 2 hours after topical administration to a human patient.
The inventor's previous U.S. Patent Publication No. 20070065463 (filed Jun. 21, 2004) discloses a topical formulation for treating migraines or cluster headaches, muscle sprains, muscle spasms, spasticity, tension headaches, tension related migraines and related conditions associated with muscle tension and pain comprising: a therapeutically effective amount of an active agent(s) incorporated into a pharmaceutically acceptable excipient for topical administration onto the skin of a human patient, the active agent(s) being selected from the group consisting of: i) an ergot alkaloid; ii) a skeletal muscle relaxant; or iii) a combination of an ergot alkaloid and a skeletal muscle relaxant; the active agent(s) being present in an effective concentration such that a unit dose of the topical formulation provides a therapeutic effect within about 2 hours after topical administration to the human patient. In certain preferred embodiments, the topical formulation comprises a skeletal muscle relaxant such as tizanidine. In certain preferred embodiments, the unit dose comprises from about 0.4 mg to 8 mg, preferably from about 0.2 mg to about 4 mg of tizanidine hydrochloride.
In instances where humans suffer from conditions involving neuronal hyperexcitability and/or a neurochemical dysfunction syndrome(s), adequate treatment is not generally available. Such conditions include headache including migraine, cluster, tension-type headache and the related menstrual conditions of menstrual migraine. In fact, other such conditions include, but are not limited to, pain, anxiety reactions, panic attacks, seizures of both epileptic and non-epileptic (psychogenic) varieties; and acute head and face pain syndromes such as trigeminal neuralgia, atypical facial pain, occipital neuralgia, TMJ related pain, hot flashes, menstrual associated dysphoria, Multiple Sclerosis, and Parkinson's Disease and similar or related syndromes.
For example, Parkinson's disease is a common, debilitating, neurological condition of unknown cause. There is no known cure and treatment is directed at reducing symptoms. It is considered the result of a progressive degenerative process within the central nervous system (CNS). A significant reduction in brain levels of the neuro-chemical dopamine is the hallmark characteristic of the disease process. Other brain chemicals are also affected. Pathological studies indicate death and loss of dopamine producing cells within the substantia nigra of the brainstem. Loss of cells in the caudate and putamen (the striatum) which rely on dopamine connections from substantia nigra, the ascending nigra-striatal dopaminergic pathway, also occurs. The resultant cardinal clinical signs of Parkinson's disease are: tremor, postural instability, bradykinesia/rigidity. Depression, autonomic dysfunction, and memory disturbance/cognitive problems are also common. Parkinson's disease is the third most common out-patient neurological diagnosis after headaches and seizures.
The mainstay treatment of Parkinson's disease is aimed at normalizing the reduced central dopamine levels. This is accomplished by either providing exogenous levodopa orally for eventual conversion into dopamine in the brain or the use of dopamine agonists to augment the endogenous dopamine. COMT inhibitors are also used in the therapeutic regimen to reduce the breakdown of dopamine, allowing for higher and more persistent levels at the receptors. The problem with these traditional therapies is that they are unable to provide the stable dopamine levels at the receptors which occur in the natural state. The fluctuations in dopamine levels result in fluctuations in clinical function: so called “on and off” states. They also affect dopamine receptor sensitivity in the long term such that “motor complications” and dyskinesias may occur after several years of therapy. This is particularly true with exogenous dopamine therapy and in patients diagnosed in their younger years.
Patients with end-of-dose wearing off phenomena, the most significant of which is “freezing”, where one is essentially paralyzed and unable to move, are significantly affected in their activities from the sudden episodic dopamine deficiency at the receptor level.
Apomorphine hydrochloride (Apokyn by Vernalis, which was recently acquired by Ipsen Pharmaceuticals) is given as subcutaneous injections to counter such “off periods”. It has also been administered via intra-peritoneal infusion. The drug is reported to take effect within 10-15 minutes and last for up to 1½ hours. This allows a patient to engage in pre-planned activities that would otherwise not have been pursued—going out to dinner, etc. The resultant sense of control over one's disease and associated reduced anxiety for such affected patients is immeasurable. Apokyn is marketed for use in the treatment of “acute, intermittent treatment of hypomobility, off episodes (end-of-dose wearing off and unpredicatable on/off episodes) associated with advanced Parkinson's disease”.
Unfortunately, as an injection, Apokyn has not been a preferred form of treatment despite its efficacy. It is also associated with a relative high cost (approximately $100 for a 3 ml cartridge) not affordable for routine use by most patients. It involves a titration phase for tolerability and efficacy determination (2 mg or 0.2 ml to 6 mg or 0.6 ml) with a nurse at a doctor's office, further contributing to cost and time. Finally, Apokyn is associated with significant nausea and vomiting to the extent patients are required to take an anti-emetic (trimethobenzamide/Tigan 200-300 mg 3×/day) for 3 days prior to the first injection and encouraged to continue the regimen for an additional 6 weeks. Despite using Tigan, a significant number of patients still experience nausea and vomiting—31% and 11% respectively in reported clinical trials. Other anti-emetics with anti-dopaminergic actions are contraindicated as they may worsen the symptoms of Parkinson's. Further, the requirement of medications to counter side-effects contributes to additional drug-drug interactions. Parkinson's patients are generally already on a significant degree of “poly-pharmacy”.
The significant nausea and vomiting associated with apomorphine in oral and injectible forms is likely the result of its direct effect on the “chemoreceptor zone” of the area postrema in the floor of the IVth ventricle adjacent to the brainstem. Other commonly reported adverse events in clinical trials also indicate stimulation of other brainstem structures, including the autonomic nervous system, by the apomorphine in the cerebral brood: dizziness, yawning, somnolence, rhinorrhea, sweating, flushing, pallor, hallucinations, edema, and chest pain.
Thus, in spite of its effectiveness and potential to improve the lives of persons affected by Parkinson's disease, for the above noted reasons, the use of injectible apomorphine has been limited. Oral forms have not been pursued as they are even less well tolerated as the dose requirements are high. Intra-peritoneal and intravenous injections are impractical.
Apomorphine hydrochloride is a non-ergoline dopamine agonist that is lipophilic and soluble in water at 80 degrees Celsius. In vitro tests show it has a high affinity for the D4 dopamine receptor and moderate for the D2, D3, and D5 receptors. It also has moderate affinity for some alpha-adrenergic receptors. It has a low affinity for the dopamine D1 and serotonin receptors. Although the precise mechanism of action of apomorphine is unknown, it is believed to work through the stimulation of post-synaptic dopamine D2 receptors in the striatum, the caudate and putamen.
The significant nausea and vomiting associated with apomorphine in oral and injectible forms is likely the result of its direct effect on the “chemoreceptor zone” of the area postrema in the floor of the IVth ventricle adjacent to the brainstem. Other commonly reported adverse events in clinical trials also indicate stimulation of other brainstem structures, including the autonomic nervous system, by the apomorphine in the cerebral blood: dizziness, yawning, somnolence, rhinorrhea, sweating, flushing, pallor, hallucinations, edema, and chest pain.
For the above reasons, despite its efficacy and potential to improve the lives of persons affected by Parkinson's disease, the use of injectible apomorphine has been limited. Oral forms have not been pursued as they are even less well tolerated as dose requirements are high. Intra-peritoneal and intravenous injections are impractical but have been pursued. Intra-peritoneal apomorphine via continuous infusion pump (such as for insulin), is used in Europe.